Polymethylenebis admantane amines

ABSTRACT

THIS APPLICATION REFERS TO POLYMETHYLENE-BIS(1-AMINOADAMANTANES) AND POLYMETHYLENEBIS(1-ADAMANTANEMETHYLAMINES) OF THE FORMULA   1-(ADAMANT-1-YL-(CH2)M-NH-(CH2)N-(CH2)M-)ADAMANTANE   WHERE M IS 0 OR 1 AND N IS 2 TO 14 WHICH ARE USEFUL IN PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF POUNDS OF THE ABOVE FORMULA WHERE N IS 10 SUCH AS (N,N&#39;&#39;DECAMETHYLENEBIS (ADAMANTANE-1-AMINE), OR (ADAMANTANE-1-METHYLAMINE) ARE PREFERRED.

United States Patent 3,629,333 POLYMETHYLENEBIS ADMANTANE AMINES DonaldClarke Boughton, Kennett Square, Pa., and Walter E. Meier, Wilmington,Del., assignors to E. I. du Pont de Nemours and Company, Wilmington,Del. No Drawing. Filed Aug. 28, 1969, Ser. No. 853,969 Int. Cl. C07c87/40 U.S. Cl. 260-563 P 2 Claims ABSTRACT OF THE DISCLOSURE Thisapplication refers to polymethylene-bis(l-aminoadamantanes) andpolymethylenebis(l-adamantanemethylamines) of the formula where m is 0or 1 and n is 2 to 14 which are useful in pharmaceutical compositionsthereof, and methods of pounds of the above formula where n is such asN,N decamethylenebis (adamantane-l-amine), or (adamantane-l-methylamine)are preferred.

BACKGROUND OF THE INVENTION This invention relates to novel compounds,their salts, pharmaceutical compositions theerof, and methods of usingpharmaceutically effective amounts of these preparations as anoreticagents.

Medical precedents have long established the use of drugs for weightcontrol. The prior art reveals two broad classes of pharmaceuticalagents especially effective for this purpose; they can loosely bedescribed as metabolism accelerators and appetite depressants.

One of the earlier known of these agents, dinitrophenol, was firstintroduced commercially in 1933. This drug effected weight loss byacceleration of metabolism in the patent. Shortly after its introductionit was discovered to be quite toxic and its use as an anoretic agent wasdiscontinued around 1935.

Another of these metabolism accelerators, thyroid U.S. PXU has long beenemployed to facilitate weight loss; however, medical authorities nowagree that its use should be limited to those patients who haveunderactive thyroids.

Some of the belladonna preparations; morphine and other narcoticanalgesics; and d-amphetamine and d-amphetamine type preparations, arerepresentative of the classes of pharmaceutical agents which purportedlyare effective appetite depressants.

Belladonna preparations are thought to inhibit appetite by causing lossof pleasure in eating; however, experiments on which these claims arebased were poorly controlled and difficult to evaluate.

Morphine and other narcotic analgesics are said to cause loss ofappetite, but are not acceptable for obvious reasons.

d-Amphetamine appears to be the best drug presently available forcontrolling appetite. d-Amphetamine-induced Patented Dec. 21, 1971weight loss is due almost entirely to reduction in food intake and onlyin small measure to increased metabolism. The target tissue of thisanoretic agent is believed to be the lateral hypothalmus of the brain.In addition to suppressing the hypothalmic centers which regulate thedesire for food, d-amphetamine causes a loss of actuity of the senses ofsmell and taste thereby making food less ap pealing.

Unfortunately, continued use of d-amphetamine often causes nervousnessand irritability as side effects; also, administration in late afternoongenerally interferes with sleep. This last side effect most severelylimits its usefulness, since most patients tend to overeat in theevening. Attempts have been made to combine d-amphetamine withsedatives; however, the problem remains unsolved.

Prolonged use of d-amphetamine is not usually possible since toleranceto the appetite depressant develops quite rapidly, and increasing thedosage ordinarily significantly exaggerates the aforementioned sideeffects.

Most authoritative evaluations of the other d-amphetamine type compoundsdo not reveal any agent superior to d-amphetamine in eithereffectiveness as an appetite depressant or in the level of undesirableside effects.

The factors of recognized medical need plus shortcomings in presentlyavailable pharmaceutical agents leads us to believe in the significanceof our invention.

SUMMARY OF THE INVENTION This invention relates to novelpolymethylene-bis(laminoadamantanes) and polymethylenebis(l-adrnantanemethylamines) which can be represented by the formula:

where m is 0 or 1 n is from 2 to 14;

pharmaceutical compositions where the active ingredient is the abovecompound or its salt; and methods of using phanmaceutically effectiveamounts of these compounds or salts, alone or in combination withnon-toxic pharmaceutical carriers, as anoretic agents in mammals.

One of the more significant aspects of this invention is thedemonstration of significant appetite depressant activity with a morefavorable therapeutic index than that of presently available anoreticagents.

Preferred pharmaceutical formulations of this invention have as theiractive ingredient a compound which can be represpented by the formula:

It also will be understood that the compounds disclosed in thisapplication have basic amino groups, which readily form salts and suchsalts having non-toxic anions are also 3 included within the scope ofthe present invention. Representative of such salts are hydrochlorides,hydrobromides, sulfates, phosphates, acetates, succinates, adipates,propionates, tartrates, citrates, bicarbonates, pamoates, cy-

4 EXAMPLE 2 N,N-hexamethylenebis(adamantan-l-amine) dihydrochloride,M.P. 331333 C., can be prepared by substituting 9.1 parts of adipolychloride for the succinyl chloride clohexyliulfamates andacetylsilhcylaies'lfof these the 5 of Example 1. The product isrecrystallized from dimethyldrochlorides, acetates and cyc ohexy sularnates are preformamide to yield 20 parts of NN, di 1 adamanty1adipferred. The cyclohexylsulfamates have ap easant taste and amide C. 7parts of thus.a.re plrtlcularlyfiseful m prepanng Syrups for Oralmantyladipamide are substituted for N,N-di-l-adarnanadmlmstratlon'.Addltlqnany the cycllfihexylsulfamatgs tylsuccinamide of Example 1 toyield 2.4 parts of N,N'- y? 1186311116831 makmg f i ta etsfifor oral a10 hexamethylenebis(adamantan-l-amine) dihydrochloride, m1n1strat1onwhich have no ob ectionable bitter taste. In M P C general, the saltsdescribed above enhance the usefulness of the relatively insolubleamines in pharmaceutical appli- EXAMPLE 3 catlons-N,N'-heptamethylenebis(adamantan-l-amine) dihydro- DESCRIPTION OF HINVENTION chloride, M.P. 322-312?1 C.,l can be prepared by slubstituting9.8 parts of pime oy ch oride for succinyl ch oride of This inventlonrelates to novel polymethylenebis-(ada- Example 1 to yield 17 parts ofNN, diamantylpimel mantan'l'elmmes) i polymethylenebls'(adamantaned'amide, M.P. 208-209 C. Diborane reduction of 7.5 parts methyl-amines)WhlCh can be represented by the formula. of the amide yields 36 Parts ofNN, heptamethylenebis 20 (adamantan-l-arnine) dihydrochloride, M.P.322423 c.

EXAMPLE 4 C C (CH2 )m ii Hank H2 mN,N'-decamethylenebis(adamantan-l-amine) dihydro chloride, M.P. 363-364C., can be prepared by substituth ing 10.2 parts of sebacyl chloride forthe succinyl chloride of Example 1 to yield 22 parts ofN,N'-di-1-adamantyl- 0 1 sebacamide, M.P. 216-217 c. Diboraue reductionof an from 2 to 8.0 parts sample of N,N-di-l-adamantylsebacamide andpharmaceutically acceptable salts thereof; and niethyields 5.4 parts ofN,N'-decamethylenebis(adamantan-lods of using pharmaceuticallyacceptable amounts of this amine) dihydrochloride, M.P. 363-364 C.compound or salts, alone or in combination with non- The following acidchlorides can be substituted for the toxic pharmaceutical carriers, asanoretic agents in marnacid chloride of Example 1 to yield thecorresponding dimals. amine salts:

Ex. Acid chloride Diamine {l 5 Oxayl chlorideN,N-ethylenebis(adamantan-l-amine)dihydrochloride, M.P.342-343 C.

6... Nonanedioyl chloride N,N-nonamethylenebis(adamantan-l-amine)dihydrochloride, M.P. 314-316 C. '1 7 Tridecanedioyl cl1lorideN,N-tridecarnethylenebis(adamantan-l-amine) dihydroohclride, dec. 341 C.

8.- D0deeandi0yl chloride N,N-dodecamethylenebis(adamantan-l-amine)dihydrochloride, dec. 3434346 0.

Tetradecanedioyl chloride..-N,N-tetradecamethyleneb1s(adamantan-l-amine) dihydrochloride, M.P.316-318" 0.

Compounds of this invention can be prepared by a method disclosed in J.Med. Chem. 11: 1103, 1968, or as described in the following examples:

EXAMPLE 1 N,N'-tetramethylenebis(adamantan-l-amine) dihydrochloride,M.P. 381-383 C., can be prepared by adding dropwise 7.2 parts ofsuccinyl chloride in parts of diethyl ether to a mixture 15 parts ofl-aminoadamantane and 10.2 parts of triethylamine in 500 parts of ether.The mixture is refluxed for 1 hour and the resultant solid is collectedby filtration. The solid is triturated with 500 parts of water, filteredand air dried. The dried solid is recrystallized from dimethylforrnamideto yield 10.3 parts of N,N-di-l-adamantylsuccinamide, M.P. 272'274 C.

The diborane generated in a separate flask by slowly adding 5.1 parts ofsodium borohydride in 125 parts of diglyme to 28.5 parts of freshlydistilled boron trifluoride in 50 parts of diglyme over a one half hourperiod is swept by a slow stream of nitrogen into a flask containing 6parts of N,N'-di-l-adamantylsuccinamide and 200 parts of refluxingtetrahydrofuran. The tetrahydrofuran is refluxed for an additional fourhours after generation of the diborane is complete. 150 parts ofmethanol are added to the tetrahydrofuran followed by saturation with.

anhydrous hydrogen chloride. The solvent is removed by heating undervacuum. The resultant solid is recrystallized from ethanol to yield 1.7parts of N,N'-tetramethylene bis(adamantan-1-amine) dihydrochloride,M.P. 381- 383" C.

EXAMPLE l0 N,N'-decamethylenebis(adamantane l methylamine)dihydrochloride, M.P. 350-35 1 C., can be prepared by adding a solutionof 9 parts of l-adamantyl chloride in parts benzene to a solutionconsisting of 50 parts pyridine, 8 parts 1,10-diaminodecane and partsbenzene. The temperature of the reaction is held below 30 C. during theaddition and then the temperature is subsequently raised to 50 C. for 1hour after the addition is complete. The reaction is poured into 500parts of water. The water layer is separated and extracted with 100parts of benzene, then discarded. The benzene portions are combined andwashed with 0.5 N-hydrochloric acid until the wash remains acidic. Thebenzene solution is next washed with 1% sodium bicarbonate solution andthen dried over anhydrous magnesium sulfate. The solvent is removedunder vacuum to yield 5.4 parts of solid amide which is then dried. Amixture of 5.4 parts of amide, 5 parts of lithium aluminum hydride and150 parts of tetrahydrofuran is refluxed for 16 hours. The excesshydride is decomposed by careful addition of saturated sodium sulfatesolution. The solid is removed by filtration. Anhydrous hydrogenchloride is passed into the solution until precipitation is complete.The solid is extracted in a Soxhlet apparatus with water. The solidprecipitating from the water in the flask is collected to yield 3.1parts of N,N-decamethylenebis(adamantane 1 rnethylamine)dihydrochloride, M.P. 350-351 C.

The following diamines can be substituted for l,l0 diarninodecane ofExample 10 to yield the corresponding products:

Ex. Diamine Product 11 EthylenediamineN,N-cthy1encbis(adamantane-l-methylamiue) dihydrochloride.

12 1,3-d am nepropaue N,N-trimethyleneb1s(adamantane-l-methylarnine)dihydroehloride.

13 l,4-d am. nobutane N,N-tetramethy1euebis(adamantane-l-methylamine)dihydrochloridc.

14 1,5-d1anunopentaue- N,N-pentauethylenebis(adamantane-l-methylamine)dihydrochloride.

15.. 1,6-d am nohexane. N N'-hexamcthy1eneb1s(adamantane-l-methylamine)dihydrochloride.

16. l,7-d iam moheptane N ,N-heptamethylenebis(adamantane-l-methylamine)dihydrochloride.

17 1,8-d am n00ctane N,N-octamcthyleneb1s(adamantane-Lmethylamine)dihydrochloride.

18.. 1,9-d1am1non0nane N,N-n0namethylenebis(adamantane-l-methylamine)dihydrochloride.

19 l,11-d am n0uudeeaneN,N-undecamethylenebis(adamantane-l-methylan1ine) dihydrochloride.

20 1,12-d aminododeeaneN,N'-dodecamethylcnebis(adamantaue-l-methylamine) dihydrochloride.

21.- 1,13-d 1am 1notridecaneN,N-tr1decamethylenebis(adamantane-l-methylamine) dihydrochloride.

22 1,14-dlarmnotetradecane.N,N-tetradceamethylenebis(adamantane-l-methylaminc) dihydrochloride.

EXAMPLE 23 The dosage admlnistered Will be dependent upon the A mixtureof 0.10 mole of N N-decamethylenebis(adahealth and weight of therecipient the kind of con. current treatment, if any, frequency oftreatment and mantan-l-amine), or (adamantane 1 meth lamine and 0.20mole of 48% hydrobromic acid is con centrat d mtenslty of anoretl?effect deslred' Gfinerany a daily and dried under Vacuum at C. to yieldN dosage of active ingredient compound will be from aboutmantan-l-amine), or (adamantane -1-methy1amine), di- 50 gg p r dose, thepreciseamount be ng ascertamable with certainty by one skilled in theart. The

hydrobromide.

The procedure of Example 23 is repeated, substituting Preferred 9 theactlve compound or Pharmaceuan equivalent amount of the indicatedreactants for those tlcal composltlon 13 from to 15 P dose of of Example23, in order to obtain the indicated acidactive ingredientadditionsalts. The activity of these. compounds as anoretic agents Ex. An incAcid Salt 24 N,N-deeamethy1enebis(adamantan-l-amine) 95% phosphoric acidN,I;11-defiartn;ethylenebis(adamantan-l-amine)bis(dihydrogen p osp a e25 Sulfuric acid N,N-dicamethy1encbis(adamantand-amine)di(hydrogensulfate). 26. Tartaric ae1dN,N-decamethyleneb1s(adamantan-l-amine)di(hydrogen tartrate). 27Perchloric acid N,N-deean1ethylencbis(adamantan-1-amine)di(perchlorate).28 Maleic acids. N,N-decamethylenebis(adamantan-l-aniine)(11(hydrogenmaleate). 2 Acetic ac1dN,N-decamethyleneb1s(adamantan-l-amine)diacetate. 30 Oitrlc acidXML-diacamcthylenebis(adamantan-1-arnine)bis(dihydrogen 01 re e 31Succinic acid N,N-decarnethylenebis(adarnantan-l-amine)disuccinate. 32.Mandellc acid. N,N-decamethyleneb1s(adamantau-1-amine)dimandelate. 33Lactic acid N,N-decamethylenebis(adamantan-l-amlne)dilactate.

As previously stated, this invention relates to the use is indicated bytesting in mice according to the method of a pharmaceutically efiectiveamount of an anoretic of Clark in Toxicol. Appl. Pharmacol. 15, 212-215agent of this invention to curb the natural appetite of 5 (1969) and indogs according to the method of Stegen,

mammals. Zsoter and Chappel in Toxicol. App. Pharmacol. 2, 589- It willbe understood that a pharmaceutically effective 601 (1960).

amount of an anoretic agent is intended to describe a The predictivevalidity of the test in mice was deterdosage of from 0.01 to mg./kg. perdose, the precise mined by comparing the effects of two knownanti-'apamount being ascertainable with certainty by one skilled 50petite drugs, d-amphetamine and phenmetrazine, with those of four drugs,chloropromazine, chlordiazepoxide,

in the art.

It will be understood that an anoretic agent is a compentobarbitol andtetrabenazine, known to cause central pound or active ingredient in apharmaceutical composinervous system depression. Data from the abovescreen tion which curbs the natural appetite of a mammal for suggeststhat this test is effective in discriminating anoretic nourishment. Thescope of the term curb is to be agents and those that manifest CNSstimulation or deviewed as pervasive of the entire spectrum of appetitepression. depression, from any restraint upon the natural food in- Thefollowing is a description of the procedure used take of the mammal tototal suppression of food intakein evaluating the compounds of thisinvention:

It will be understood that mammal includes any of METHOD a class ofhigher vertebrates that nourish their young with milk secreted bymammary glands and have skin usually more or less covered with hair.

The compounds or pharmaceutical compositions of this gray opaque plasticholding cages for 13 days prior to invention can be administered in theanoretic treatment test. The animals are given continual access to foodand of this invention by any practical means that delivers apharmaceutically effective amount of the active compound of thisinvention to those areas of the central nervous system and/or otherareas within the body which are be- On the day of the appetite test themice are deprived lieved to control the mammals intake of food. Althoughof food for 24 hours. The animals are moved into an parenteraladministration of the compound or pharmaceuexperimental room, dividedinto groups of 5 each and tical composition may be desirable in somesituations, put into white translucent plastic boxes. The mice areingestion of the active compound, either in a pharmaceunot given anyfood or water when they are in these boxes. tical composition alone orin some dietetic food or bev- After a 60-minute period the mice areremoved from erage appears to be the more preferred method of admintheboxes, weighed and then orally dosed with either istration. compound orcontrol vehicle on a blind basis. After Female mice, of roughlyequivalent weight, are divided mental) temperature is maintained at 76F. :2 F. The room lights are on from 6 AM. to '8 RM. each day.

into groups of 25 each and housed in a holding room in Water during thisperiod. Room (holding and experi- Each feeding chamber contains 2 brassbars into each of which 10 holes have been milled (hole diameter= Adistance between centers of 2 adjacent holes=% hole depth=0.180"). Eachhole is about half-filled with 0.05 ml., (:5%) of a 50% aqueous solutionof sweetened condensed milk. The bars are loaded by means of anautomatic pipette connected to a 10-tube manifold that divides the totalvolume of milk into 10 equal parts. After 5 minutes in the feedingchamber the mice are again observed for signs of abnormal activity.Since the control animals are invariably active at this time one canreadily detect a decrease in spontaneous motor activity, which isindicative of compound-induced depression. The mice remain in thefeeding chamber for 45 minutes at which time a count is made of thenumber of milk drops consumed, estimated to the nearest 0.025 ml.

All compounds are prepared in a PVA-acacia vehicle (polyvinyl alcohol1%, acacia 5% and methylparaben 8 0.1% in Water) and administered orallyat a constant volume of 0.01 1111/ g. of body weight. Groups of 10 to100 mice are treated at the dosage levels indicated in the table. Dosesare expressed as milligram (mg.) of base compound weight per kilogram(kg) of animal body weight. Eighty mice serve as control animals andreceive the PVA-acacia vehicle alone.

RESULTS The accompanying table shows (1) the effect of each dose of eachcompound on milk consumption in mice expressed as a percentage of themilk intake of the control animals (Control Mean=0.45 mL/mouse), (2.)the dosage value which is estimated to cause a 50% reduction in milkconsumption, Anti-Appetite ED50), (3) the dosage estimated to causesigns of stimulation in 50% of the mice (Stimulant ED50) or depressionin 50% of the mice (Depressant ED50) and (4) the ratio of the Stimulantor the Depressant ED50 to the Anti-Appetite ED50. This ratio value isthought to predict the relative separation between doses that will causeloss of appetite and doses that will cause CNS stimulant or depressantside eifects in test subjects. All ED50 values are determined accordingto the method of Litchfield and Wilcoxon (Litchfield, J. T., J r. andWilcoxon, F.: A Simplified Method of Evaluating Dose-Efiect Experiments.J. Pharm. Exptl. Therap., 1949, 96, 99-113).

Anti- No. Oral dose Appetite 1 Mg. of base compound weight/kg. mousebody weight.

2 Ratio of Stimulant ED or Depressant ED to Anti-Appetite ED. 3Milliliters/gram.

' of or ED (Percent Percent Percent Compound mice (mg/kg.) of control)stimulated depressed Ratio 1 PVA-Vehiele (Control) 80 3 0.01 4 100 16 0N, N -tetradeeanmethy1ene bis (adamantan-1-amine) dihydroehloride 10 12.5 65 10 0 N, N-decamethylenebis (adamantan-l-amine) dihydrochloride 1. 087 21 0 4O 4. 0 91 19 0 20 12. 5 68 10 0 40 16.0 39 16 5 20 25. 0 36 105 6. 4, 7. 2 20 50. 0 26 5 25 40 64. 0 19 30 20 100. 0 9 0 10 256. 0 1330 N, N-hexamethy1enebis(adamantan-l-amine) dihydrochloride- 30 1. 0 9426 0 30 4. 0 109 20 0 10 12. 5 69 0 30 30 16. 0 52 36 0 10 25.0 40 0 04. 4 10 50. 0 22 30 30 30 64. 0 23 46 10 100. 0 10 0 10 256. 0 0 0 N,N'-tetramethy1ene bis(adamautan-1-amine) dihydrochloride 30 1. 0 85 16 030 4. 0 102 13 0 30 16. 0 49 23 0 6 1 30 64. 0 28 43 10 256.0 0 0 100 N,N-decamethylene bis (adamantanemethyl-l-amine) dihydroehloride 10 12. 572 0 0 d-Amphetamine 100 0. 25 82 20 0 100 0.50 68 28 0 1 7 Thecompounds of this invention show promise for use as anoretic agents dueto the demonstration of significant appetite depressant capacity inaddition to a more favorable therapeutic index than that of thepresently available weight reduction preparations.

The active ingredient for this invention can be employed in usefulcompositions according to the present invention in such dosage forms astablets, capsules, powder packets, or liquid solutions, suspensions, orelixirs, for oral administration. In such compositions the activeingredient will ordinarily always be present in an amount of at least0.2% by weight based on the total weight of the composition and not morethan 99% by weight.

Besides the active ingredient of this invention the composition willcontain a solid or liquid non-toxc pharmaceutical carrier for the activeingredient.

In one embodiment of a pharmaceutical composition of this invention, thesolid carrier is a capsule which can be of the ordinary gelatin type. Inthe capsule will be from about l99% by Weight of a polymethylenebis-(adamantan-l-amine) or polymethylenebis(adamantanel-methylamine) and99-1% of a carrier. In another embodiment, the active ingredient istableted with or without adjuvants. In yet another embodiment, theactive ingredient is put into powder packets and employed. Thesecapsules, tablets, and powders will generally constitute from about 1%to about 99% and preferably from to 90% by weight of active ingredient.These dosage forms generally contain from about 1 to about 500milligrams of active ingredient, with from about 10 milligrams to about250 milligrams preferred.

As mentioned above, oral administration can be in a suitable suspensionor syrup, in which the active ingredient generally will constitute fromabout .02 to 10%, and preferably about 0.2 to 5% by Weight. Thepharmaceuti cal carrier in such composition can be a watery vehicle suchas an aromatic water, a syrup or a pharmceutical mucilage.

Suitable pharmaceutical carriers are described in RemingtonsPharmaceutical Sciences by E. W. Martin, a wellknown reference text inthis field.

In addition to the exemplary illustrations above, the following examplesfurther explain one aspect of the present invention:

EXAMPLE 34 A large number of unit capsules are prepared for oraladministration by filling standard two-piece hard gelatin capsules eachwith 50 milligrams of a powdered polymethylenebis(adamantan 1 amine oradamantane-lmethylamine), 175 milligrams of lactose, 5 milligrams ofmagnesium stearate, and milligrams of talc.

EXAMPLE 35 .A large number of unit capsules are prepared for oraladministration by filling soft gelatin capsules with a solution of apolymethylenebis(adamantan-l-amine or adamantane-l-methylamine) insoybean oil.

EXAMPLE 36 A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 25 milligrams of activeingredient, 4 milligrams of gelatin, 4 milligrams of magnesium stearate,5 milligrams of starch, 5 milligrams of microcrystalline cellulose andmilligrams of mannitol. Slow release tablets can also be used, byapplying appropriate coatings.

A large variety of compositions according to this invention can thusreadily be made by substituting other compounds for this invention, andincluding specifically but not limited to compounds for this inventionthat have specifically been named hereinbefore. The compounds will beused in the amounts indicated in accordance with procedures well knownand described in the Martin text mentioned above.

It is claimed:

1. A compound of the formula:

where m is 0 or 1 n is from 2 to 14; or pharmaceutically acceptableacid-addition salts of said compounds. 2. The compounds of claim 1,wherein the compounds are of the formula:

References Cited UNITED STATES PATENTS 3,523,137 8/1970 Moore 260558ALEX MAZEL, Primary Examiner D. R. PHILLIPS, Assistant Examiner US. Cl.X.R.

260-50l.2, 557 R; 424-3l6, 325

